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Receptors and Protein-Protein Interaction -----signal transduction proteins Primary messenger Extracellular ♣. Cellular activities are regulated by cell surface receptors and other intracellular signaling proteins. Cytosol ECM: ExtraCellular Matrix Secondary messenger Cellular activity changes ♣. Different cells have different ECM ♣. Protein-protein interaction plays a very important role in signal transduction. Intracellular signaling ♣. Many diseases are directly caused by erratic signaling. Functional enzymes Intracellular signaling is also very important of regulation of cellular functions. Fearon, E. R. Science, 1997, Vol. 278, 1043-1050 1. Primary messengers. B. Proteins: Epidermal Growth Factor (EGF) A. Hormones Many other growth factors, Interferon, insulin, hGH, etc. C. Other stimuli: such as light Many others 2. Receptor 1: Epidermal growth factor (EGFR), single transmembrane protein Tyrosine kinases form a receptor superfamily 2. Receptor 2: human growth hormone receptor (hGHR), single transmembrane protein hGHR hGH hGH P P JAK2 JAK2 JAK2 P P STAT pathway 2. Receptor 3: insulin receptor (INSR), dimeric transmembrane protein 2. Receptor 4: GABA receptor, dimeric protein (α2β2) with 4 membrane-spanning helices per subunit. GABA receptor Chemical synapse: signaling by neurotransmitters cAMP 2. Receptor 5: Adrenergic receptor, single protein with 7 membrane-spanning helices Typical of G-protein coupled receptors, another superfamily of signaling proteins. G-proteins: guanyl nucleoside binding (GNP) proteins GPCR: G-protein coupled receptors 2. Receptor 6: Light receptor 7 membrane-spanning helices Mediated by bound retinal (Vitamin A) Light absorption 2. Receptor 7: Intracellular steroid receptors Intracellular signaling protein: RAS GDP GNRP inactive GTP RAS RAS RAS GDP active GTP Pi GAP G12V, G12D, G12R Cancerous mutations G13V Q61H, Q61L > 30% cancers contain constitutive active RAS Steroid receptors 3. Secondary messenger 1: cAMP 3. Secondary messenger 2: Ca2+ •. Mediated by calcium-binding proteins such as calmodulin Ca2+-Calmodulin complex •. Intracellular Ca2+ ~ nM, inactive when increased to ~1 µM, Ca –complex formed •. Conformation change increases its affinity for the target proteins. •. Involved in many intracellular signalling pathways exemplified by phosphoinositide cascade and muscle contraction Conformation change 3. Secondary messenger 3: Serotonin DAG and IP3 R activation Phospholipase C 3. Secondary messenger 4: Many others, cGMP, 4. Relevance to drug development Disease state: 1. Abnormal level of hormones, Such as GABA ⇔ Epilepsy seizures, convulsions 2. Abnormal receptors Insulin desensitization ⇔ Type II diabetes 3. Abnormal intracellular signal transduction proteins Constitutive active RAS ⇔ cancers; Erratic tyrosine kinases ⇔ cancers and other diseases Intervention in Receptor Signaling and Protein-Protein Interaction Disease states: A. Abnormal level of hormones, Such as GABA ↓ ⇔ Epilepsy seizures, convulsions Adjust hormone level by metabolic intervention Adjust hormone level by agonists and antagonists. B. Abnormal receptors Insulin desensitization ⇔ Type II diabetes Mutations: usually fatal C. Abnormal intracellular signal transduction proteins Constitutive active RAS ⇔ cancers; Erratic tyrosine kinases ⇔ cancers and other diseases Inhibition of kinase activities, break down protein-protein interaction 1. Indirect intervention of the signaling pathways: A. Interfere in the metabolism of the hormones or messengers Example: GABA A negative neurotransmitter ⇔ glutamate (positive neurotransmitter) GABA ↓ ⇒ convulsion, related to epilepsy, Huntington’s disease, Parkinson’s disease, and tardive dyskinesia Inhibit GABA-AT, GABA ↑ Inhibit GAD, GABA ↓ 1. Indirect intervention of the signaling pathways: B. Direct administration of the hormone or messenger molecules Example 1: Parkinson’s disease Dopamine ↓ OH Example 2: Administration of hGH to adults to increase height. Example 3: Use of estrogen in cosmetics. HO 17β−Εstradiol 2. Direct intervention of the signaling pathways: Agonist: an agent that can evoke a maximal response like the endogeneous ligand (hormone or messenger). Antagonist: an agent that binds the receptor and produce no response. Competitive: binding the same site as the messenger. Noncompetitive: binding a different site but affect the binding of an agonist. Partial agonist: between an agonist and an antagonist, it produces a response less than the maximum. Binding and potency of an agonist or antagonist Dose-response curve for Acetylcoline (Ach) and its receptor Response: muscle contraction Dose-response curves [agonist] = 0 Antagonist Partial agonist [agonist] = low Competitive Antagonist Partial agonist Noncompetitive Antagonist [agonist] = high Partial agonist Drug-Receptor interactions Agonist Partial agonist or antagonist Noncovalent interactions: Antagonist Drug structural features Chirality Geometric isomers Conformational isomers Ring topology + Van der Waals interaction Examples of agonists and antagonists Agonist: Similar to the natural ligand. Antagonist: Resemble the natural agonist but structurally different. Development of Analgesics from morphine 3. Intervention of protein-protein interaction PDB code: 3HHR Interface at site 1: 30 AA side chains on each protein 1300 Å2 ∆G = -12.3 kcal/mol, KD < 0.1 nM Ref: De Vos et al. Science 1992, 264, 306-313 Clackson et al. Science 1995, 267, 383-386 Atwell et al. Science 1997, 278, 1125-1128 Drugs targeting signal transduction pathways 1. Very effective. 2. Many side effects because too much is involved 3. Specificity/selectivity is essential. 4. Drugs intervening protein-protein is expected to be more specific. More reading materials: A. Levitzki, Protein Kinase Inhibitors as a Therapeutic Modality, Acc. Chem. Res. 2003, 36, 462-469. Gadek TR. et al. ‘Generation of an LFA-1 antagonist by the transfer Of the ICAM-1 immunoregulatory epitope to a small molecule’ Science 2002, 295, 1086-1089